The international microbiological and infectious disease community continues to express serious concern that the continuing evolution of antibacterial resistance could result in bacterial strains against which currently available antibacterial agents will be ineffective. The outcome of such an occurrence could have considerable morbidity and mortality.
The effectiveness of currently available therapies is limited by highly resistant infectious strains such as methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug resistant (MDR) strains of Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumonia, and other Enterobacteriaceae. Such resistant bacteria are major causes of patient morbidity and mortality. Helfand, β-lactams Against Emerging ‘Superbugs’: Progress and Pitfalls, Expert Rev. Clin. Pharmacol. 1(4):559-571 (2008).
Acinetobacter baumannii has emerged globally as a cause of many serious infections such as urinary tract infections, wound and surgical site infection, bacteremia, meningitis, and nosocomial infections, including ventilator-associated pneumonia (VAP). Lee, et al., Impact of Appropriate Antimicorbial Therapy on Mortality Associated with Acinetobacter baumannii Bacteremia, Clinical Infectious Diseases, 55(2):209-215 (2012); Yang, et al., Nosocomial meningitis Caused by Acinetobacter baumannii: Risk Factors and Their Impact on Patient Outcomes and Treatments, Future Microbiology, 7(6):787-793 (2012). VAP is the most frequent A. baumannii infection in intensive care unit (ICU) patients, with a mortality rate of 25-75%. Chaari, et al., Acinetobacter baumannii Ventilator-Associated Pneumonia: Epidemiology, Clinical Characteristics, and Prognosis Factors, Int. J. Infectious Diseases, 17(12):e1225-e1228 (2013). About 63% of A. baumannii isolates are considered multi-drug resistant (MDR), which severely limits the treatment options, and which drives the high mortality rate. Karageorgopoulos, et al., Current Control and Treatment of Multi-Drug Resistant Acinetobacter Infections, Lancet, 8(12):751-762 (2008).
A major driver to the MDR resistance seen in the clinic is the increasing prevalence of extended-spectrum beta-lactamases (ESBLs). β-lactamases are enzymes that are secreted by some bacteria and can open the β-lactam ring of a β-lactam antibiotic and thereby deactivate it. There are currently four classes of β-lactamases, denoted Class A, Class B, Class C and Class D, in the Ambler classification. Class A, Class C and Class D β-lactamases are serine β-lactamase inhibitors, while Class B β-lactamases are metallo-β-lactamases (MBLs). Bush & Jacoby, Updated Functional Classification of β-Lactamases, Antimicrobial Agents and Chemotherapy, 54(3):969-976 (March 2010); Ambler, R. P., The Structure of Beta-Lactamases, Philos. Trans. R. Soc. London B; 289:321-331 (May 1980).
To help improve the effectiveness of β-lactam antibiotics, some β-lactamase inhibitors have been developed. However, typical β-lactamase inhibitors in many instances are insufficient to counter the constantly increasing diversity of β-lactamases. Most currently available β-lactamase inhibitors have activity primarily against certain Class A enzymes, which severely limits their utility. Additionally, new β-lactamase inhibitors, such as avibactam (approved in the US in 2015) and relebactam (MK-7655, still in clinical trials) work primarily on Class A and C enzymes, with minimal effectiveness against Class D β-lactamases. Bebrone, et al., Current Challenges in Antimicrobial Chemotherapy: Focus on β-Lactamase Inhibition, Drugs, 70(6):651-679 (2010).
Sulbactam is the Class A β-lactamase inhibitor (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide. In addition to being a β-lactamase inhibitor, it also has intrinsic activity against a few pathogens, including Acinetobacter baumannii. Currently, sulbactam is commercially available in the United States in combination with ampicillin, which is marketed as Unasyn® and is approved in the US for treatment of skin, gynecological and intra-abdominal infections; it is also sold in the US as an oral agent Sultamicillin®. Adnan, et al., Ampicillin/Sulbactam: Its Potential Use in Treating Infections in Critically Ill Patients, Int. J. Antimicrobial Agents, 42(5):384-389 (2013). Clinically, Unasyn® has been used to treat VAP, bacteremia and other nosocomial infections caused by A. baumannii, even though ampicillin has no activity against the pathogen. However, significant resistance is emerging in the clinic. Jones, et al., Resistance Surveillance Program Report for Selected European Nations, Diagnostic Microbiology & Infectious Disease, 78(4): 429-436 (2011). Sulbactam is also commercially available in certain regions of the world in combination with cefoperasone and is sold as Cefina-SB®, Sulperazone® or Bacperazone®, depending on the geographic region.
While sulbactam is itself a β-lactamase inhibitor, it does not possess activity against many clinically relevant β-lactamases such as TEM-1 and Klebsiella pneumonia carbapenemases (KPCs), in addition to having no activity against most Class C and Class D β-lactamases. See Table 1. This upsurge in resistance means that sulbactam will have less and less clinical efficacy for patients with Acinetobacter spp. infections.
Imipenem/cilastatin is a broad-spectrum antibiotic with activity against many Gram-negative and Gram-positive organisms, including, but not limited to, Acinetobacter spp., Citrobacter spp., Escheriachia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella spp., Morganella morganii, Pseudomonas aeruginosa, Enterobacter spp., Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumonia, Streptococcus pyogenes, Enterococcus faecalis, Clostridium spp., and Bifidobacterium spp., among others. However, resistance to imipenem is emerging, especially in Pseudomonas aeruginosa infections. See, e.g., Lautenbach, et al., “Imipenem Resistance in Pseudomonas aeruginosa: Emergence, Epidemiology and Impact on Clinical and Economic Outcomes”, Infect. Control Hospital Epidemiol., (2010) 31(1):47-53. Resistant strains of Pseudomonas aeruginosa to carbapenems such as imipenem have been increasing, and are associated with longer hospital stays, increased healthcare spend and higher mortality. See Liu et al., “Influence of Carbapenem Resistance on Mortality of Patients with Pseudomonas aeruginosa Infection: a Meta-Analysis”, Nature: Scientific Reports (2015), 5:11715.
There is a clear and urgent need for a treatment for infections caused by resistant, and MDR, bacterial infections, which already have a high mortality rate, and which will only prove more deadly as resistance to current treatments grows.